Two important parameters related to the efficaciousness of drugs are the “therapeutic index” (also known as the “therapeutic ratio”) and the “therapeutic window”. The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Quantitatively, it is the ratio given by the dose required to produce the toxic effect divided by the therapeutic dose. A commonly used measure of therapeutic index LD50 divided by ED50. The therapeutic window is a parameter for estimation of drug dosage which can treat disease effectively while staying within the safety range. It is the range between the ED50 and the starting point of LD50 curve. It is believed that adjustment of this parameter can help to avoid most of the potential side effects.
Pharmaceuticals with narrow therapeutic windows are common and are frequent in groups such as, for instance, antiarrhythmics, anticonvulsants, cardiac glycosides, aminoglycosides, cytotoxics, and immunosuppressants.
A large majority of antitumor agents have a very narrow therapeutic window. One way of improving the therapeutic index of such agents is to use suitable infusion regimens. Ideally, the drug concentration is maintained inside the therapeutical window for a desired time range, after which it quickly leaves the body. Prolonged infusions have in general showed god efficacy with few side effects. For instance prolonged infusion is the most efficient way to reduce cardiotoxicity of doxorubicin, one of the mostly used anticancer drugs. However, prolonged infusions (sometimes up to 72 hours) are expensive and inconvenient. Accordingly, great efforts have been made to mimic such infusions by the use of drug delivery systems which can ensure slow release of the active ingredient from various kinds of drug depots. Drug delivery systems comprising such depots are usually provided by way of encapsulation of drugs into nanoparticle of various polymers, polymerosomes, liposomes, or microemulsions.
However, in order to protect itself against hostile intruders of different kind (such as viruses, bacteria and fungal spores) human and animal bodies have developed mechanisms to remove or disintegrate particles larger than about 50 nm. The Reticulo-Endothelial System (RES), a part of the immune system, is the most effective destructor of such particles. The probability for a particle to be targeted by RES increases dramatically with increasing particle size.
Many drugs are provided in a cationic amphiphilic form, such as for instance drugs that have one or more amino groups in their structure. In acid environment these drug substances are transformed into salts, e.g. hydrochlorides, sulphates, lactates or tartrates, and exist predominantly in a protonated form. These transformations increase the solubility of the drugs in aqueous solutions and make it possible to use these solutions for i.v. infusions. After infusion the environment is switched to slightly basic as pH of blood is approximately 7.4, which results in deprotonation of the drugs. This in turn reduces the solubility of the substances, which improves the PK/PD properties of the drug by increasing the grade of protein binding, accelerating penetration of the substances into cells as well as decreasing renal clearance. A lot of antineoplastic drugs are provided in a cationic amphiphilic form, and the described way of administration is applied for drugs as, for instance, doxorubicin and its analogues (epirubicin, daunorubicin, idarubicin), vinca alkaloids (vinblastine, vincristine, vinorelbine), amsacrine, mitoxantrone, topotecan and irinotecan.
US 2004048923 describes a group of retinoids including among numerous others the sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester and the sodium salt of N-(13-cis-retinoyl)-L-cysteic acid methyl ester. It is stated that the substances make it possible to manufacture new micelle formulations of poorly soluble pharmaceutical compounds like paclitaxel and docetaxel. The teaching of US 2004048923 does not aim for the provision of formation of smaller nanoparticles with decreased water solubility and improved encapsulation capacity.